Despite the publication of studies of HIV patients correlating the presence of immune complexes with disease progression (Schechter M. T. et al., Susceptibility to AIDS Progression Appears Early in HIV Infection, AIDS, 1990; 4:185-90; and Ellaurie M., et al., Human Immunodeficiency Virus (HIV) Circulating Immune Complexes in Infected Children, AIDS Res. Hum. Retro., 1990; 6(12):1437-41), the mechanism of immune complex-mediated CD4 depletion is not clearly understood. Depletion of CD4 cells is correlated with a negative outcome.
Antibody-dependent cellular cytotoxicity (ADCC) mediated by either monomeric IgG or immune complexes may also play a protective role in the HIV patient, by lysing infected cells. If the relative roles for ADCC in the control of viral load (protection) and CD4 cell decline (immunopathogenesis) are delineated, then strategies for intervention and modulation of these effects can be considered. The extent of natural antibodies to the CD4 binding site of gp120 is likely to influence the relative roles of protective versus pathogenic effects of ADCC. Definition of the time courses of protection and of pathogenesis will allow for rational testing of potential therapies. Cytokines such as interleukin-2 (IL-2), to enhance lysis of infected cells could be attempted during periods of low circulating levels of gp120 and low infected cell burden, as demonstrated by Kovacs J. A. et al., (Increases in CD4 T Lymphocytes With Intermittent Courses of IL-2 in Patients With Human Immunodeficiency Virus Infection, N Eng J. Med., 1995; 332:567-575). In addition, for patients experiencing periods of high levels of circulating gp120, specific therapy with CD4 binding site antibodies, to bind free gp120 and prevent adsorption to uninfected CD4 cells, could be tested. Results of a placebo-controlled trial of passive therapy with hyperimmune plasma demonstrated a treatment benefit on CD4 cell count, supporting the potential use of such antibody therapy (Levy J. et al., Passive Hyperimmune Plasma Therapy in the Treatment of Acquired Immunodeficiency Syndrome: Results of a 12-month Multicenter Double-Blind Controlled Trial, Blood, 1994; 84(7):2130-35). Recent data on single dose studies of IL-12 in humans suggests that reses in both NK activity and in the number of cells bearing NK markers results from this intervention (Jacobson, M A et al., 1996, 3rd Conference on Retroviruses and Opportunistic Infections. Abstract 309). This would suggest similar cautions against the use of this cytokine in patients with high viral loads; in such patients, circulating gp120-coated uninfected and infected CD4 cells, which may not be lysed by NK cells in the absence of oxogenous stimulants, may be rapidly lysed during therapy with IL-12.